The invention is directed to novel compounds that bind to sodium channels and modulate their activity. The invention is also directed to pharmaceutical compositions comprising such compounds, methods of using such compounds to treat diseases associated with the activity of sodium channels, and processes and intermediates useful for preparing such compounds.
Voltage-gated ion channels play a critical role in the electrical activity of neuronal and muscle cells. Large families of voltage-gated ion channels (e.g. sodium channels) have been identified. These ion channels have been the target of significant pharmocologic study, due to their potential role in a variety of pathological conditions.
For example, the activity of sodium channels has been implicated in numerous pathological conditions, including neuropathic pain. Neuropathic pain is a chronic condition associated with diabetes, chronic inflammation, cancer and herpes virus infection. An estimated 75 million people worldwide are expected to suffer from neuropathic pain by the year 2010. Unfortunately, current treatment options typically provide only partial pain relief, and are limited by inconvenient dosing and by side effects, such as somnolence, ataxia, edema, gastrointestinal discomfort and respiratory depression.
Thus, despite the limited success that has been achieved using sodium channel modulators to treat pain, there continues to be a need for novel agents and methods that are useful for treating neuropathic pain, as well as other conditions associated with the activity of sodium channels. Particularly useful agents may be more potent or cause fewer side effects than existing agents.
The present invention provides novel compounds that bind to sodium channels and modulate (e.g. block) their activity. Accordingly, the invention provides a compound of the invention, which is compound of formula I: 
wherein:
Q is xe2x80x94Oxe2x80x94, xe2x80x94S(O)m, xe2x80x94(CR5R6)pxe2x80x94, xe2x80x94O(CR5R6)rOxe2x80x94, or xe2x80x94N(Rk);
each R1 is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, or Ra;
each R2 is independently a covalent bond or alkylene; wherein alkylene is optionally substituted with 1 to 4 substituents independently selected from Rb;
each X is independently oxy (xe2x80x94Oxe2x80x94) or xe2x80x94N(Rm)xe2x80x94;
each Y is independently NRnRp or a heterocyclyl containing at least one nitrogen atom, wherein each nitrogen of the heterocyclyl is substituted with R3 or is linked to R2, and wherein each heterocycle of Y is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R4;
each R3 is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, oxo, or heterocyclyl; and each R4 is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, or Rb; or R3 and R4 are joined to form a C1-4 alkylene group, wherein the alkylene group is optionally substituted with 1 to 4 substituents independently selected from Rb;
each R5 and R6 is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; or R5 and R6 together with the carbon atom to which they are attached form a ring having from 5 to 7 ring atoms, wherein the ring optionally contains 1 or 2 heteroatoms in the ring independently selected from oxygen, sulfur or nitrogen;
wherein for R1-R6, each alkyl, alkenyl, and alkynyl is optionally substituted with Rx, or with 1, 2, 3, or 4 substituents independently selected from Rb; for R1-R6, each aryl and heteroaryl is optionally substituted with 1 to 4 substituents independently selected from Rc, and for R1-R6, each cycloalkyl and heterocyclyl is optionally substituted with 1 to 4 substituents independently selected from Rb and Rc;
each Ra is independently xe2x80x94ORd, xe2x80x94NO2, halo, xe2x80x94S(O)mRd, xe2x80x94SRd, xe2x80x94S(O)2ORd, xe2x80x94S(O)mNRdRe, xe2x80x94NRdRe, xe2x80x94O(CRfRg)nNRdRe, xe2x80x94C(O)Rd, xe2x80x94CO2Rd, xe2x80x94CO2(CRfRg)nCONRdRe, xe2x80x94OC(O)Rd, xe2x80x94CN, xe2x80x94C(O)NRdRe, xe2x80x94NRdC(O)R, xe2x80x94OC(O)NRdRe, xe2x80x94NRdC(O)ORe, xe2x80x94NRdC(O)NRdRe, xe2x80x94CRd(xe2x95x90Nxe2x80x94ORe), xe2x80x94CF3, or xe2x80x94OCF3;
each Rb is independently Ra, oxo or xe2x95x90Nxe2x80x94ORe;
each Rc is independently Ra, alkyl, alkenyl, or alkynyl; wherein each alkyl, alkenyl and alkynyl is optionally substituted with 1 to 4 substituents independently selected from Rb;
each Rd and Re is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; wherein each alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with 1 to 4 substituents independently selected from Rh; or Rd and Re together with the atoms to which they are attached form a heterocyclic ring having from 5 to 7 ring atoms, wherein the heterocyclic ring optionally contains 1 or 2 additional heteroatoms independently selected from oxygen, sulfur or nitrogen;
each Rf and Rg is independently hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; wherein each alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with 1 to 4 substituents independently selected from Rh; or Rf and Rg together with the carbon atom to which they are attached form a ring having from 5 to 7 ring atoms, wherein the ring optionally contains 1 or 2 heteroatoms independently selected from oxygen, sulfur or nitrogen;
each Rh is independently halo, C1-6 alkyl, C1-6 alkoxy, aryl, (aryl)-C1-6 alkyl, heteroaryl, (heteroaryl)-C1-6 alkyl, hydroxy, amino, xe2x80x94NHC1-6 alkyl, xe2x80x94N(C1-6 alkyl)2, xe2x80x94OC(O)C1-6 alkyl, xe2x80x94C(O)C1-6 alkyl, xe2x80x94C(O)OC1-6 alkyl, xe2x80x94NHC(O)C1-6 alkyl, xe2x80x94C(O)NHC1-6 alkyl, carboxy, nitro, xe2x80x94CN, or xe2x80x94CF3;
Rk is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; wherein each alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with 1 to 4 substituents independently selected from Rh;
Rm is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; wherein each alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with 1 to 4 substituents independently selected from Rh;
each Rn and RP is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; wherein each alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with 1 to 4 substituents independently selected from Rh; and
each Rx is independently aryl, heteroaryl, cycloalkyl or heterocyclyl; wherein each aryl or heteroaryl is optionally substituted with 1 to 4 substituents selected from the group consisting of Rc, and wherein each cycloalkyl and heterocyclyl is optionally substituted with 1 to 4 substituents selected from Rb;
m is 0, 1, or 2;
n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
p is 1, 2, or 3;
r is 2, or 3; and
each w is independently 0, 1, 2, 3, or 4;
or a pharmaceutically-acceptable salt thereof;
provided that when any Y is NRnRp or a nitrogen-linked heterocyclyl, then the R2 attached to that Y is not a covalent bond or methylene.
The invention also provides a pharmaceutical composition comprising a compound of the invention and pharmaceutically acceptable carrier.
The invention also provides a method of treating a disease or condition associated with sodium channel activity (e.g. neuropathic pain) in a mammal, comprising administering to the mammal, a therapeutically effective amount of a compound of the invention. The invention also provides a method of treating a disease or condition associated with sodium channel activity (e.g. neuropathic pain) in a mammal, comprising administering to the mammal, a therapeutically effective amount of a pharmaceutical composition of the invention.
The invention also provides processes and intermediates described herein, which are useful for preparing compounds of the invention.
The invention also provides a compound of the invention as described herein for use in medical therapy, as well as the use of a compound of the invention in the manufacture of a formulation or medicament for treating a disease or condition associated with sodium channel activity (e.g. neuropathic pain) in a mammal.
Preferred compounds of the invention are the compounds of formula I shown in Table I below.